Promising investigational therapy improves survival in aggressive childhood brain tumor
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An international team of investigators has identified a drug candidate that nearly doubles survival rates for patients with diffuse midline glioma, an aggressive type of childhood brain tumor.
Researchers at the University of Michigan Rogel Cancer Center and the Chad Carr Pediatric Brain Tumor Center led the team. In a study published in Cancer Discovery, the researchers reported on two clinical trials evaluating the compound, ONC201, in 71 patients with H3K27M-mutated diffuse midline gliomas.
“This patient population has historically been very difficult to treat,” Carl Koschmann, MD, associate professor of pediatrics and clinical scientific director of the Chad Carr Pediatric Brain Tumor Center at Michigan Medicine, told Healio. “We can use radiation, and that does help sow down the tumor, but you can’t remove the tumor by surgery due to the fact that they infiltrate critical structures of the brainstem and the inner and middle sections of the brain. There have been hundreds of clinical trials in this patient population that have yet to move the needle.”
Koschmann spoke with Healio about the current prognosis for diffuse midline gliomas, how his team discovered ONC201, and his hopes for the drug’s potential to improve treatment of this disease.
Healio: How did your team discover ONC201, and what is its mechanism?
Koschmann: ONC201 is an oral medicine with a known ability to get into the brain, and in preclinical cell culture models, it is effective in a number of tumor types. As a community of pediatric brain tumor physicians, we fell into it a bit by luck. There was an early-phase trial of adult glioblastoma in which the drug was found to be safe and could get into the brain, but was not effective against the tumor. However, there were a few younger patients who had the H3K27M mutation who did better than expected on that medication. Because of that, a phase 1 study was started at NYU and our center participated. What we found over the course of this study was that not only does it seem to have a signal of efficacy in these patients, we were also able to sort out why it was working specifically in these tumors.
Healio: Why did it work?
Koschmann: These tumors are epigenetically changed to be very different from normal brain cells. The mutation found in these tumors — named H3K27M — disrupts the way DNA is expressed in tumor cells. This makes them distinct from brain cells, and also very aggressive. ONC201 severely changes the metabolism of cancer cells. It disrupts how the mitochondria works, which are the gas tank of the cells. These tumors are unique because the disruption of metabolism changes the regulation of DNA expression, or epigenetics, of the tumor cells, making them less malignant. It’s that metabolic effect on epigenetics that’s unique to this tumor. We think that is why ONC201 wasn’t as effective in adults with glioblastoma, because they didn’t have that epigenetic change.
We first noticed the connection between metabolism and epigenetics through spinal fluid that we had taken from some of our treated patients. What we saw was different patterns of spinal fluid changes in the metabolites based on whether patients were responding to the drug. This led myself and my colleague, Sriram Venneti, MD, PhD, to look into what the metabolic changes were doing to the epigenetics, and it has also given us some insight into biomarkers we might be able to use on patients being treated right now, to look for that signal in the spinal fluid.
Healio: What did you find in terms of overall survival?
Koschmann: We found an average overall survival of 21 months for patients treated after initial radiation and prior to disease progression. Prior to that, the average survival for this patient population was somewhere between 12 and 15 months. For a given patient being diagnosed right now, 21 months is certainly not enough, but we’re optimistic this shows that this tumor is vulnerable, and that there are treatments that can help. Our ongoing work will be to build on that success.
Healio: What is next in your plans to study this drug?
Koschmann: We have an ongoing trial through a consortium called the Pacific Pediatric Neuro-Oncology Consortium (PNOC). In the PNOC DMG-ACT trial, we have arms consisting of other treatments or treatment modalities added to ONC201to see if they’re more effective than ONC201 by itself. In the coming years, we expect to add on immunotherapies and other targeted drugs, and possibly treatments like focused ultrasound on top of ONC201.
Healio: What are your hopes for the long-term potential of this drug?
Koschmann: The scientific community and the families of these patients are ready for this drug to be approved and available, and we would like it to be established as a standard of care for use after radiation. That way, we can build onto that with other therapies.
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For more information:
Carl Koschmann, MD, can be reached at University of Michigan Health, 1540 East Hospital Dr. Floor 7 Reception C, Ann Arbor, MI 48109; email: ckoschma@med.umich.edu.
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